<i>In Vivo</i> Comparison of CHX-DTPA Ligand Isomers in Athymic Mice Bearing Carcinoma Xenografts

Roselli, Mario; De, Milenic; Mw, Brechbiel; Mirzadeh, Saed; Cg, Pippin; Oa, Gansow; Colcher, David; Schlom, Jeffrey

doi:10.1089/cbr.1999.14.209

Cited by 20 publications

(14 citation statements)

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“…The CHX-A″-DTPA conjugate has been reported to be more suitable when radio-metallo-nuclides are coupled to a MAb. 35,36 Both cDTPA and CHX-A″-DTPA, coupled to PAI2, were investigated in this study. We found that there was no significant difference in kidney accumulation between the two chelators up to four hours (five half-lives of 213 Bi).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Song¹,

Rizvi²,

Qu³

et al. 2007

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Song¹,

Rizvi²,

Qu³

et al. 2007

Cancer Biology & Therapy

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“…(61)(62)(63). In our prior studies, 3a was conjugated with mAbs against antigens on canine hematopoietic cells, then radiolabeled with 213 Bi and evaluated in dogs (20,21,38).…”

Section: Discussionmentioning

confidence: 99%

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At

et al. 2007

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We are investigating the use of recombinant streptavidin (rSAv) as a carrier molecule for the shortlived α-particle emitting radionuclides 213 Bi (t 1/2 = 45.6 min) and 211 At (t 1/2 = 7.21 h) in cancer therapy. To utilize rSAv as a carrier, it must be modified in a manner that permits rapid chelation or bonding with these short-lived radionuclides, and also modified in a manner that diminishes its natural propensity for localization in kidney. Modification for labeling with 213 Bi was accomplished by conjugation of rSAv with the DTPA derivative p-isothiocyanato-benzyl-CHX-A″ (CHX-A″), 3a. Modification for direct labeling with 211 At was accomplished by conjugation of rSAv with an isothiocyanatophenyl derivative of a nido-carborane (nCB), 3b, or an isothiocyanatophenyldPEG ™ /decaborate(2-) derivative, 3c. After conjugation of the chelating or bonding moiety, rSAv was further modified by reaction with an excess (50-100 equivalents) of succinic anhydride. Succinylation of the lysine amines has previously been shown to greatly diminish kidney localization. rSAv modified by conjugation with 3a and succinylated radiolabeled rapidly with 213 Bi (< 5 min), providing a 72% isolated yield. 211 At labeling of modified rSAv was accomplished in aqueous solution using chloramine-T as the oxidant. Astatination of rSAv conjugated with 3b and succinylated occurred very rapidly (<1 min), providing a 50% isolated radiochemical yield. Astatination of rSAv conjugated with 3c and succinylated was also very rapid (<1 min) providing 66-71% isolated radiochemical yields. Astatination of succinylated rSAv, 2a, which did not have conjugated borane cage moieties, resulted in much lower radiolabeling yield (18%). The 213 Bi-or 211 At-labeled modified rSAv preparations were mixed with the corresponding 125 I-labeled rSAv, and dual-label in vivo distributions were obtained in athymic mice. The in vivo data show that 213 Bi-labeled succinylated rSAv [ 213 Bi]6a has tissue concentrations similar to 125 I-labeled modified rSAv [ 125 I] 6b, suggesting that 213 Bi is quite stable towards release from the chelate in vivo. In vivo data also indicate that the 211 At-labeled rSAv conjugated with 3b or 3c and succinylated are stable to in vivo deastatination, whereas succinylated rSAv lacking a boron cage moiety is subject to some deastatination. The modified rSAv conjugated with nido-carborane derivative 3b has a higher retention in many tissues than rSAv without the carborane conjugated. Interestingly, the rSAv conjugated with 3c, which also contains a m-dPEG 12 ™ moiety, has significantly decreased concentrations in blood and other tissues when compared with direct labeled rSAv, suggesting that it may be a good candidate for further study. In conclusion, rSAv that has been modified with CHX-A″ and succinylated (i.e. 5a) may be useful as a carrier of 213 Bi. The encouraging results obtained with the PEGylated decaborate(2-) derivative 3c and succinylated (i.e. 5c) suggests that its further study as a carrier of 211 At in pretargeting prot...

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“…Several backbonesubstituted derivatives of isothiocyanatobenzyl-DTPA have been described for use in radioimmunoconjugates radiolabeled with 88 Y or 111 In. [20][21][22]37,38 In the present study, the in vivo behavior of immunoconjugates radiolabeled with 206 Bi, using six DTPA-derivatives, were compared to assess their potential for radioimmunotherapy with the a-emitters, 212 Bi and 213 Bi.…”

Section: Discussionmentioning

confidence: 99%

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

Milenic¹,

Roselli²,

Mirzadeh³

et al. 2001

Cancer Biotherapy and Radiopharmaceuticals

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Among the radionuclides considered for radioimmunotherapy, alpha-emitters such as the bismuth isotopes, 212Bi and 213Bi, are of particular interest. The macrocyclic ligand, DOTA, has been shown to form stable complexes with bismuth isotopes. The kinetics of the complexation of bismuth with the DOTA chelate, however, are slow and impractical for use with 212Bi and 213Bi that have half-lives of 60.6 and 45.6 min. The study described herein compares six DTPA derived bifunctional chelates with the goal of identifying an alternative to the DOTA ligand for radiolabeling with bismuth. Radioimmunoconjugates comprised of MAb B72.3, each of the six DTPA chelates, and radiolabeled with 206Bi, which facilitated the evaluation due to its readily detectable gamma-emission. In vitro studies showed that each of the radioimmunoconjugates retained immunoreactivity that was comparable to its 125I-labeled counterpart. The 206Bi- and 125I-labeled immunoconjugates were then co-injected i.p. into normal athymic mice. Injection of Afree@ 206Bi demonstrated that the kidneys were the critical organ to evaluate for retention of bismuth in the chelate complex. Major differences were identified among the six preparations. The CHX-A and -B immunoconjugates were found to have 1) the lowest %ID/gm in the kidney; 2) a level of 206Bi in the kidney that was comparable to that of 125I-B72.3; and 3) no significant uptake of 206Bi evident in other organs such as bone, lung and spleen. The results described herein suggest that either of the cyclohexyl derivatives of DTPA may be suitable candidates for the labeling of immunoconjugates with alpha-emitting bismuth isotopes for radioimmunotherapeutic applications.

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In Vivo Comparison of CHX-DTPA Ligand Isomers in Athymic Mice Bearing Carcinoma Xenografts

Cited by 20 publications

References 3 publications

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

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In Vivo Comparison of CHX-DTPA Ligand Isomers in Athymic Mice Bearing Carcinoma Xenografts

Cited by 20 publications

References 3 publications

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Pharmacokinetics and toxicity of 213Bi-labeled PAI2 in preclinical targeted alpha therapy for cancer

Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides 213Bi and 211At

In VivoEvaluation of Bismuth-Labeled Monoclonal Antibody Comparing DTPA-Derived Bifunctional Chelates

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Streptavidin in Antibody Pretargeting. 5. Chemical Modification of Recombinant Streptavidin for Labeling with the α-Particle-Emitting Radionuclides ²¹³Bi and ²¹¹At